Ifosfamide, chemically 3-(2-chloroethyl)-2-(chloroethylamino)-tetrahydro-2H-1,3,2-oxazaphosphorin -2-oxide, is a member of the oxazaphosphorin class of alkylating cytostatic antitumor agents. Ifosfamide was included in a series of cytostatic compounds disclosed and claimed by Arnold et al., in U.S. Pat. No. 3,732,340 which issued May 8, 1973.
Ifosfamide is soluble in water slightly in excess of 10 percent by weight. The aqueous solution however remains stable for only a few days when stored at room temperature. The anhydrous form of ifosfamide is a white crystalline powder which melts in the range 48.degree. to 51.degree. C. Because the anhydrous solid form begins to sinter below its melting point, as well as being hygroscopic, the drug should be protected from heat and humidity. Additional problems have been encountered due to other characteristics of the ifosfamide drug substance, and inventive pharmaceutical compounding and processing improvements have been disclosed.
U.S. Pat. No. 4,882,452 issued Nov. 21, 1989 to Engel, et al., claims particularly characterized crystalline ifosfamide and processes for its preparation. This form of ifosfamide had superior dry flow properties which improved vial-filling processes for the anhydrous form of the drug.
In U.S. Pat. No. 4,952,572, Sauerbier, et al. disclosed sealed vials of concentrated non-aqueous solutions of ifosfamide for further dilution with water for parenteral administration.
Due to problems such as short shelf-storage of these solid and solution forms of ifosfamide, lyophilized formulations have been disclosed and claimed as having improved storage life as well as being particularly well suited for the preparation of injectable solutions of ifosfamide.
Sauerbier, et al., disclosed lyophilized ifosfamide-hexitol compositions in European Patent Application EP 265,812, published May 4, 1988. The lyophilizates were claimed to be superior to dry crystalline ifosfamide for use in filled vials for reconstitution. Mannitol was the preferred hexitol component in the lyophilizate composition. Sauerbier, et al., have also disclosed and claimed in U.S. Pat. No. 4,959,215, lyophilized ifosfamide-hexitol compositions additionally containing mesna, which functions as a uroprotectant. Again the preferred hexitol was mannitol.
Earlier, Alexander, et al., in U.S. Pat. No. 4,537,883 had disclosed and claimed hydrated mannitol lyophilizates comprising the oxazaphosphorin, cyclophosphamide. Urea was disclosed as an unsuitable primary excipient in those compositions. Recently Alam, et al., in U.S. Pat. No. 5,036,060 disclosed and claimed a mannitol-free lyophilized formulation of cyclophosphamide in which sodium chloride served as the primary excipient.
The lyophilizate compositions of the present invention which comprise ifosfamide; urea; and optionally, mesna; exhibit improved stability with superior dissolution characteristics and enhanced appearance in comparison with dry ifosfamide powder, nonaqueous concentrated solutions or previous lyophilizate compositions of ifosfamide. It was unexpected that urea as a primary excipient would impart superior stability for an ifosfamide lyophilizate compared to other excipients, especially hexitols. Alexander, et al. in U.S. Pat. No. 4,537,883 reported that mannitol was superior to urea as well as most other pharmaceutical excipients as the primary excipient in cyclophosphamide lyophilizate compositions. Of greater relevance, Sauerbier, et al. disclosed the preference of hexitols, especially mannitol, as the primary excipient in ifosfamide lyophilizate compositions.